Antisperm antibodies: Do antisperm antibodies bound to spermatozoa alter normal reproductive function?

Extensive investigations have been conducted to evaluate the potential role of antisperm antibodies (ASA) in infertile men and women. It was originally demonstrated in 1932 that injection of spermatozoa into the peritoneal cavity of female guinea pigs could induce temporary sterilization (Baskin, 1932). In the male and female, ASA may be found systemically (in the blood and lymph) and in local secretions (in seminal or cervico–vaginal fluids) (Kutteh et al., 1995). Antibodies in the blood and lymph belong predominantly to the immunoglobulin G (IgG) isotype, while those found in external secretions are predominantly of the IgA isotype (Marshburn and Kutteh, 1994; Mazumdar and Levine, 1998). Many questions still remain on the role of ASA in reproduction (Table I). Indeed a recent survey of the diagnosis and management of ASA in the UK indicated little consensus in testing methods, significant levels, and management of ASA (Krapez et al., 1998). Of particular concern in this age of in-vitro fertilization (IVF) are ASA that may affect the fertilizing capability of male spermatozoa. Autoantibodies to spermatozoa are detected in sera, in seminal plasma, and on spermatozoa. Theoretically, tight junctions between Sertoli cells in the testis form a `blood–testis' barrier which prevents the formation of autoantibodies to spermatozoa. Any break in this barrier (such as after vasovasotomy or genital tract infection) may result in the production of ASA. However, in men, antibodies bound to spermatozoa are not correlated with seminal fluid ASA or ASA in sera (Bronson et al., 1987). The question of which test to use for the detection of ASA has previously been discussed (Marshburn and Kutteh, 1994; Helmerhorst et al., 1999). These detection methods can be divided into three major categories: (i) those which cause agglutination of spermatozoa; (ii) those which cause immobilization of spermatozoa; and (iii) those which detect antibodies specific for spermatozoa. Although there is no consensus, the immunobead test (IBT) and the mixed agglutination reaction (MAR) have emerged as the most frequently-used tests (Krapez et al., 1998). In evaluating these methods, one has to consider the source of the sperm antigens. If whole spermatozoa are used, only antibodies directed against antigens contained on the sperm cell surface will be detected. Alternatively, if disrupted or solubilized spermatozoa are used, an entirely different set of antigens will be exposed. Antibodies against these `internal' antigens may not be of biological significance. Another factor influencing these tests is the isotype of detected antibodies (IgG, IgA, or IgM). In some tests IgM is measured; this isotype is found infrequently and in low concentrations in the male reproductive tract (Yeh et al., 1995). Others do not measure IgA, the predominant class of antibody found in secretions. An ideal assay for ASA would indicate the location of an antibody (tail-directed or head-directed), would detect each isotype of immunoglobulin (IgG, IgM, and IgA), and would be able to determine a significant level of ASA binding. ASA may result in a state of subfertility but would rarely prevent fertility completely in couples (Dondero et al. 1979; Marshburn and Kutteh, 1994). Proposed treatments for subfertility secondary to sperm-bound ASA have evolved in several directions (Table II). These treatments include: (i) methods to reduce the production of ASA (condom use); (ii) processing spermatozoa to decrease the effect of ASA (washing, enzymatic treatment); (iii) separation of ASA bound spermatozoa from non-bound spermatozoa (split ejaculate, depletion); (iv) suppression of antibody production (steroids); and (v) overcoming possible ASA interference (insemination, IVF). Each of these therapies has its advocates. However, in recent years, treatment has advanced to IVF and intracytoplasmic sperm injection (ICSI). There are many proposed mechanisms for ASA-mediated infertility, but most are thought to act via impairment of processes that lead to oocyte fertilization and embryo development (Haas, 1996). Original studies with sperm-bound with ASA demonstrated decreased penetration of the zona pellucida (Haas et al., 1980). Experimental data indicate several possible sites where ASA may interfere with IVF (Table III). A number of studies have been reported which demonstrate the effect of sperm-bound ASA on fertilization rates after IVF (Table IV). The majority of these studies appear to indicate deleterious effects of sperm-bound ASA on oocyte fertilization rates, embryo quality, or implantation. However, the majority of the studies that demonstrated deleterious effects were retrospective analyses in patients who had poor fertilization on one cycle of IVF. In most studies, couples with low oocyte fertilization rates and ASA were compared to couples with normal fertilization rates who did not have impaired infertility. Thus, by the design of the study, one would expect significant differences in oocyte fertilization rate, implantation rate, and pregnancy rate (Clarke et al., 1997). Relatively few of these studies were performed using a study group tested for ASA in a prospective fashion with selection of control and study patients before the IVF outcome had been determined (Mandelbaum et al., 1987; Sukcharoen and Keith, 1995; Culligan et al., 1998). Interestingly, none of these three studies demonstrated an adverse effect of ASA on IVF (Table IV). However, these three studies could be criticized, as their positive criteria for ASA was only >15 or 20% IgG or IgA. World Health Organization guidelines (1992) indicate that `probably significant' levels of ASA are found at >50% binding IgG or IgA. In the absence of clear scientific data concerning sperm-bound ASA, most IVF centres have established policies based on their best interpretation of available data. The policy at our unit for the last 2 years has been to screen all male partners for direct ASA (using IBT) prior to IVF. If either IgG or IgA ASA are >50% we have counselled the couple and suggested that half of the oocytes should undergo ICSI. Of course, if other indications for ICSI are present, e.g. prior IVF cycle with <20% fertilization, or low sperm parameters, ICSI would be performed on all oocytes (Hamberger et al., 1998). Using this strategy, we identified 14 men with ≥50% IgG or IgA ASA out of 215 cases (6.5%), however, there were eight men who otherwise would not have shown indications for ICSI. From these eight couples, four benefited by enhanced fertilization with the ICSI procedure and the other four had no benefit when comparing ICSI with conventional fertilization. In the absence of clear scientific data, many practitioners have used cost effectiveness to determine the usefulness of certain medical strategies. Using the method reported previously (Culligan et al., 1998), the cost-benefit ratio of our protocol was calculated. The cost of ASA testing was $21 500 ($100×215 patients) plus the additional charge of ICSI ($1000×eight cases) for a total cost of $29 500. When evaluated based on the four individuals who benefited by ICSI, the total cost per case was $7375 ($29 500 ÷ four couples). An alternative policy might be not to test anyone for sperm-bound ASA and to treat everyone with conventional IVF, unless there were other indications for ICSI. If failed fertilization cycles occurred, a subsequent cycle would be treated with ICSI (as is standard in many centres). If this alternative strategy was used in our centre, the total cost would have been $33 500 for four IVF–ICSI cycles ($8375×four couples). For a programme of our size the choice of which strategy to use is not clear. Thus, based on the reports summarized above and our own personal experience, therapy for the majority of cases of sperm-bound ASA-associated infertility remains empiric and largely unproven. Questions concerning antisperm antibodies (ASA) bound to spermatozoa Questions concerning antisperm antibodies (ASA) bound to spermatozoa Proposed therapies for male antisperm antibodies (ASA) Proposed therapies for male antisperm antibodies (ASA) Possible sites that sperm-bound antisperm antibodies (ASA) interfere with in-vitro fertilization Possible sites that sperm-bound antisperm antibodies (ASA) interfere with in-vitro fertilization Effect of sperm-bound antisperm antibodies (ASA) on in-vitro fertilization. Values in parentheses are precentages Effect of sperm-bound antisperm antibodies (ASA) on in-vitro fertilization. Values in parentheses are precentages